J-alkylateb-z-amino-s



United States Patent Oil 3,158,5Zl Patented Feb, 2,1965

This invention relates to 3-alkylated-2-amino-5,6-poly- 5 methylene-4(3H)-pyrimidinones and a process for the manufacture thereof. More particularly, this invention provides new and inherently useful chemical compounds of the formula N f TNHQ (H2 n t wherein Z represents a hydroxyalliyl or allcynyl radical and n represents a positive integer less than 3. 7

Among the hydroxyalkyl and alkynyl radicals represented by Z, those containing more than 1 and fewer than 4 carbon atoms. are preferred, i.e., hydroxyethyl, hydroxypropyl, ethynyl, and propynyl groupings. Less optimally adapted to present purposes but also comprehended by Z are other hydroxyalkyl and allrynyl radicals which may be thought of as deriving, respectively, by substitution of l or more hydroxylsfor hydrogen in a lower alkyl radical and by elimination of appropriate hydrogen from a lower alkyl radical (excluding the methyl grouping, of course) in favor of a triple bond. Those skilled in the art will recognize that lower alltyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isohutyl, sec-butyl, tertbutyl, pentyl, neopentyl, hexyl, isohexyl, heptyl, and like monovalent saturated, acyclic, straightor branched-chain,

hydrocarbon groupings of emperical formula wherein n represents a positive integer less than 9.

It will be further recognized by those skilled in the art that Z-aminopyrimidine derivatives of the type with which we are here concerned can and do reversibly tautcrnerize to corresponding imines, thus 1 T fi-NH; :NH

M H M (Hz ni unwP l l the proportion of the two tautomers present in any given circumstance being dependent upon the physical state of the substance involved, and its environment: whether it be solid or liquid and, if dissolved, in what solvent and at what pH. Accordingly, the naming and enformulation of the subject compounds as 2-amines and not Z-imines is a matter of convenience only; both tautomeric forms are within the ambit of the described invention.

Equivalent to the foregoing amine bases of this invention for the purposes here described are corresponding non-toxic acid addition salts of the formula r wherein Z and n retain the meanings previously assigned; T represents 1 equivalent of an anionfor example, chloride, bromide, iodide, nitrate, phosphate, sulfate, sulfamate, methyl sulfate, ethyl sulfate, benzenesulfonate toluenesulfonate, acetate, lactate, succinate, malate, maleate, tartrate, citrate, gluconate, ascor'bate, benzoate, cinnarnate, or the like-which, in combination with the cationic portion of a salt aforesaid, is neither pharmacologically nor otherwise undesirablein pharmaceutical dosage; and x represents a positive integer less than 4, its precise value depending upon the number of basic nitrogen atoms involved in salt formation.

The compounds towhich this invention relates are useful as chemical intermediates and by reason of their valuable pharmacological properties. Thus, for example, they are 'anti-ulcerogenic, pepsin-inhibitory, and antihypercholesterolemic.

Manufacture of the claimed compounds proceeds by heating an appropriate 2 4 amino 5,6 polyrnethylenepyrimidin-4-ol with a selected alkyl halide Z-Br in a solution of sodium methoxide in methanol. meanings of n and Z remain as before.)

Conversion of the basic amines of this invention to corresponding acid addition salts is accomplished by mix ing the base with from 1 to 3 equivalents, ,asindicated, of any of various inorganic and strong organic acids, the anionic portion of which conforms to T as hereinabove defined. a

The following examples describe in detail compounds il- (The lustrative of the present invention andmethods which have 2-amin0-6,7-dihydro-3-(2 hydroxyethyl) 5H cyclopenta[d]pyrimidin-4(3H)-0nc.--To a solution of 7 parts of sodium methoxide in 350 parts of methanol is added 15 parts of 2-amino-6,7-dihydro-SH-cyclopenta [d]pyrimidin 4-0], followed by 16 parts of 2-bromoethanol. The re sultant mixture is maintained with agitation at room temperature for 1 hour, then heated at the boiling point under reflux with continued agitation overnight. Solvent is thereupon removed by vacuum distillation and the residue suspended in a solution of 10 parts of sodium hydroxide in 1000 parts of water. After 2 hours, insoluble solids are filtered 01f, washed on the filter with water until the washings are neutral to litmus, dried in air, and recrystallized from methanol. The recrystallized material, Washed with ether, is 2-amino-6,7-dihydro-3-(Z-hydroxyethyl) -5H-cyclopenta [d l pyrimidin-4 3H -one melting at approximately 249. The product has the formula N-CHzGHzOH Example 2 detailed, 2-amino-6,7-dihydroXy-3-(Z-hydroxypropyl 5H- cyclopenta[d]pyrimidin-4(3H)-one, having the formula UCFECHEOH Example 4 2-amin0-6,7-dihydr0-3 propynyl 5H cyclopenmla] pyrimidin-4(3H)-0ne.Substitution of 16 parts of 3- bromo-l-propyne for the 2-bromoethanol called for in Example 1 afiords, by the procedure there detailed, 2- amino 6,7 dihydro 3 propynyl 5H cyclopentald] pyrimidin-4(3H)-one melting at 238240. The product has the formula Example 5 N-OH CECH 2-amin0-5,6,7,8-tetmhydr0-3-propynyl 4(3H) quinaz0lin0ne.Substitution of 16 parts of 2-amino-5,6,7,8- tetrahydro-4-quinazolinol and 16 parts of 3-bromo-lpropyne for the 2-amino-6,7-dihydro-5H-cyclopenta[d] pyrimidin-4-ol and 2-bromoethanol, respectively, called for in Example 1 afiords, by the procedure there detailed, Z-amino-S,6,7,8-tetrahydro-3-propynyl 4(3H) quinazolinone melting at 216-218". The product has the formula What is claimed is: 1. A compound of the formula N fi $NHZ (H2 FU wherein R represents a member of the group consisting of radicals of the formulas alkyleneOH -CH CECH in which the alkylene radical called for contains more than 1 and fewer than 4 carbon atoms and n represents a positive integer less than 3.

2. A compound of the formula HQQ N-alkylene-OH wherein the alkylene radical called for contains more than 1 and fewer than 4 carbon atoms and n represents a positive integer less than 3.

3. 2-amino-6,7-dihydro-3-(Z-hydroxyethyl)-5H cyclopenta [d] pyrimidin-4 3H) -one.

4. Z-amino-S,6,7,8-tetrahydro 3 (2 hydroXyethyD- 4(3H)-quinazolinone.

5. A compound of'the formula.

wherein n represents a positive integer less than 3'.

6. 2-amino-6,7-dihydro-3-propynyl-5H cyclopentaEd] pyrimidin-4(3H)-one.

7. 2-amino-5,6,7,S-tetrahydro-3-propynyl-4(3H) quinazolinone.

References Cited in the file of this patent UNITED STATES PATENTS 2,517,824 Appelquest Aug. 8, 1950 2,621,162 Baker Dec. 9, 1952 2,969,361 Thompson Jan. 24, 1961 3,007,938 Kirchner Nov. 7, 1961 OTHER REFERENCES Grout et al.: Jour. Chem. Soc., pages 35405 (1960). 

1. A COMPOUND OF THE FORMULA 